The Mechanism of Disease of Tri-Nucleotide Repeat Expansion Diseases (P9-11.002)

Abstract

<h3>Objective:</h3> To clarify the mechanism of disease of tri-nucleotide repeat (<b>TNR</b>) expansion diseases such as Huntington’s Disease, Myotonic Dystrophy and Friedreich’s Ataxia. <h3>Background:</h3> The current explanation for TNR expansion diseases is DNA slippage during DNA duplication; however, it does not explain why risk of disease starts with 30–40 TNRs or 90–120 repetitive nucleotides and occurs in non-dividing neurons. An alternative explanation is that (1) TNRs are mutation-prone; (2) a constant environmental factor induces constant DNA damage and mutations independent of DNA duplication; and (3) existing DNA repair mechanisms are prone to fail starting at 90–120 repetitive nucleotides. <h3>Design/Methods:</h3> TNR sequences were evaluated for the presence of mutation-prone DNA: GC-rich sequence and somatic hypermutation (<b>SHM</b>) hotspots. Environmental factors able to cause constant DNA damage independent of geographic location or time were investigated. Existing DNA repair mechanisms were assessed for likelihood of failure at or above a TNR sequence of 90–120 repetitive nucleotides. <h3>Results:</h3> All TNR sequences consist of GC-rich DNA or SHM hotspots. Among environmental factors only oxidative stress from minimum ionizing particle (<b>MIP</b>) radiation has the energy spectrum, constant presence, and geographic distribution required to cause double-strand DNA breaks in unwound, single-strand DNA during transcription. Homologous recombination repair is a repair mechanism for double-strand DNA breaks that is present in terminally differentiated neurons at time of active transcription; it requires the immediate presence of template duplex DNA to initiate repair synthesis. With increasing TNRs, the size of the D-loop template (average length 200 nucleotides) may be larger (often) or smaller (rarely) than the actual number of damaged repeats, explaining expansion or contraction of TNRs in successive generations. <h3>Conclusions:</h3> The combination of mutation-prone GC-rich DNA or SHM hotspots, MIP radiation-related oxidative stress as constant source of mutations, and a DNA repair mechanism that fails with long stretches of TNRs explains the etiology of TNR expansion diseases. <b>Disclosure:</b> The institution of Prof. De Groen has received research support from Pfizer. The institution of Prof. De Groen has received research support from NIH. Prof. De Groen has received intellectual property interests from a discovery or technology relating to health care. Prof. De Groen has received personal compensation in the range of $500-$4,999 for serving as a Invited speaker at annual conference x2 with AAFPE. Prof. De Groen has received personal compensation in the range of $0-$499 for serving as a None with None.